Emerging role of heme and heme degradation products in the modulation of cardiac ion channels

项目概要/摘要 在过去的几年里，来自地球仪的研究集中在红肉的消费和风险上。 心血管疾病这种正相关性与过量的血红素及其降解有关 铁（Fe 2+），这是丰富的红肉。血红素作为一种稳定的辅因子， (Fe2+）与卟啉-IX配位，通常赋予气体敏感性，如细胞色素中所例示的， 血红蛋白、肌红蛋白和可溶性鸟苷酸环化酶。系统中过量的血红素被血红素分解代谢 加氧酶，其产生一氧化碳（CO）、铁和胆绿素。然而，新出现的证据表明， 提出了血红素功能的新范式;细胞内游离血红素可以作为一种有效的非基因组急性 能够直接调节离子通道蛋白的信号分子。尽管可能的生理和 血红素和其他血红素衍生分子的病理生理作用，我们对急性 在心血管系统中血红素信号传导的靶/效应物受到严重限制。这项提案的目的是 确定血红素和血红素降解产物（CO）对心血管功能的影响， 1）血红素和一氧化碳如何影响心脏离子通道？2)过量的血红素和CO 改变心肌细胞的线粒体自噬

PROJECT SUMMARY/ABSTRACT Over the past years, research from around the globe has focused on the consumption of red meat and the risk of cardiovascular disease. This positive correlation has been linked to excess heme and its degradation product iron (Fe2+), which are abundant in red meat. Heme serves as a stable cofactor consisting of an iron (Fe2+) coordinated to a porphyrin-IX, often conferring gas sensitivity as exemplified in cytochromes, hemoglobin, myoglobin, and soluble guanylyl cyclase. Excess heme in the system is catabolized by heme oxygenase, which produces carbon monoxide (CO), iron and biliverdin. Emerging evidence, however, suggests a new paradigm of the heme function; intracellular free heme can act as a potent non-genomic acute signaling molecule capable of directly regulating ion channel proteins. Despite the probable physiological and pathophysiological role of heme and other hemp-derived molecules, our knowledge of the acute targets/effectors of heme signaling in the cardiovascular system is severely limited. The goal of this proposal is to define the impacts of heme and heme degradation products (CO) on cardiovascular function by addressing the following questions 1) How do heme and CO impact cardiac ion channels? 2) Does excess heme and CO alter mitophagy in cardiac cells?